Herpes Simplex virus (HSV) can cause a wide range of diseases, including skin lesions, which are common, encephalitis which is rare, an HSV infection of the eye, which is a leading cause of blindness in the USA (400,000 cases). The seroprevalence of HSV in the U.S. adult population is very high (approximately 70%). Herpes virus infections are characterized by the ability of the virus to form latent infections in the nervous system. It is this ability, which leads to recurrent episodes of the disease causing much human suffering, which is the focus of our application. The overall goal of this proposal is to understand the mechanism of HSV latency using both a mouse model system and tissue culture studies. We have previously used a mouse model system of HSV latency to study physical state of the latent viral genome, and to initiate studies on viral gene expression during latency. From our data, we have formulated models for the mechanism of HSV-1 latency. We now wish to continue to refine these models using the techniques of molecular virology. The program consists of three scientific projects, and an administrative and two scientific cores. The scientific projects are titled: 1. Gene Expression during HSV-1 Latency and Reactivation; 3. The Role of Cellular Transcription Factors in the Regulation of HSV-1 Latency and Reactivation; 4. Herpes Simplex Virus and Neuronal Cell Interactions. Successful completion of these studies will permit the mechanisms of HSV latency to be described in more detail, allowing formulation of new strategies for the prevention of latency and recurrence. In addition, it is anticipated that the knowledge gained will continue to be of use to the fields of gene therapy and cancer therapy in the nervous system, and continue to provide more patentable findings.